HIV and Hepatocellular Carcinoma. Dr Kosh Agarwal Institute of Liver Studies King s College Hospital Rome May 2013

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1 HIV and Hepatocellular Carcinoma Dr Kosh Agarwal Institute of Liver Studies King s College Hospital Rome May

2 In theory, there is no difference between theory and practice In practice there is Chuck Reid

3 Case Incidence Risk factors for HCC Screening for HCC Treatment Options Dante s Inferno/ D Brown! 3

4 47yrs old woman (Hispanic) CASE 1994 HIV diagnosed 1996 HCV diagnosed 1998 CD4 count 342 cells/µl (HAART started) 2004 CD4 count above 400cells/µl and HIV RNA undetectable HCV genotype 1a and DNA d appt s for 3yrs to co-infection clinic 2003 Peripheral stigmata of cirrhosis (spider naevi, palmar erythema, cryoglobulin associated rash) US liver- showed splenomegaly Low platelet count 6- monthly liver ultrasound scans for HCC surveillance Treatment offered for HCV but patient declined until Jan

5 April 2007 Nov 2007 Jan 2008 CASE non-responder to HCV antiviral therapy, discontinued Liver transplant assessment MRI Liver 2 HCC 14mm and 27mm in left lobe MELD 14 CPB Radio-frequency ablation March 2008 New hepatic mass July 2008 AFP 56,766 IU/ml MRI Liver multiple hepatic masses and metastases to abdominal wall Palliative care as per patient s wishes Sept 2008 Died aged 61 yrs old (at time CD4 count 451cells/µl and HIV RNA >75 copies/ml ) 3

6 Hepatocellular Carcinoma Patients have two diseases - with independent natural histories Cirrhosis 75-90% of all HCCs arise in a cirrhotic liver All types of cirrhosis may develop HCC Removal of the cause of cirrhosis doesn t remove the risk of HCC

7 Incidence Estimated 33 million people infected with HIV worldwide Joint UN Programme on HIV/AIDS 2010 Global report 50% of HIV patients on HAART do not die of AIDS Weber et al. Arch Intern Med 2006; 166: In HIV positive patients 11.9% of non-aids defining cancer deaths due to HCC In HIV postive patients HCC prevalence rates are 82/10,000 cases (according to data collection on adverse events of anti HIV drugs) HCV co-infection strongest predictor of death in US veterans Study Ioannou et al. Hepatology 2013; 57 (1):

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9 2004 GICAT study 41 cases vs 384 HIV -ve controls younger, sicker, poor survival, little Rx offered however 15/41 within Milan! 3

10 Risk factors for HCC Age Chronic and occult HBV infection Chronic HCV infection Diabetes Non-alcoholic fatty liver disease HIV-1 TAT protein expression 10

11 Age and survival of HIV infected patients with HCC Braü et al. AASLD, Boston 2010, Poster #

12 Age and HCC in HIV-Infected Patients Compared to younger HIV-infected patients with HCC, patients 50 years 1. are more frequently black 2. tend to have chronic hepatitis C 3. tend to present more frequently with multiple rather than solitary tumors 4. tend to receive effective HCC therapy less often 5. tend toward shorter survival (p= 0.11) Braü et al. AASLD, Boston 2010, Poster #

13 HBV infection 5-15 fold increase in risk of HCC in chronic HBV carriers El-Serag et al. Liver Disease: from bench to bedside-post graduate course, 2004, p % of HIV infected patients are chronic HBV carriers Puoti et al. AIDS 2004; 18: Occult HBV infection (i.e. Lack of chronic hep B surface antigen but HBV DNA positive) ranges from 10% of HIV patients with anticore IgG ab in ACTG cohort and 89.5% in Swiss cohort Shire et al. J Acquir Immune Defic Syndr 2004; 36: Hofer et al. Eur J Clin Microbiol Infect Dis 1998; 17:

14 HCC incidence in patients with HBV cirrhosis treated with ETV All patients Cirrhotics Cumulative development rates of HCC (%) HCC Log-rank test P < % 4.0% 0.7% 1.2% 13.7% 10.0% 2.5% 3.7% Control ETV Cumulative development rates of HCC (%) % 4.8% 2.6% HCC 20.9% 12.2% 4.3% 28.5% 19.7% 7.0% 38.9% 22.2% 7.0% Control ETV LAM No. at risk ETV Control Treatment duration, years No. at risk ETV LAM Control Treatment duration, years Hosaka T et al. Hepatology 2012 Dec 5. doi: /hep

15 Long term therapy with TDF decreased incidence of HCC vs predicted risk 6-year long-term follow-up from pivotal TDF studies compared with predicted rate of HCC using the REACH-B model Validated in both cirrhotic ad non-cirrhotic patients Progressive divergence after 3.3 years Kim et al. EASL 2013 Years

16 Chronic HCV infection Rate of fibrosis progression is accelerated in HIV-HCV conifected patients compared to HCV monoinfection Benhamou et al. Hepatology 1999; 30: HIV-HCV coinfected patients with HCC are younger than those HCV monoinfected Sahasrabuddhe et al. Cancer 2012; 118: Time from HCV infection to HCC is shorter in HIV-HCV coinfected patients Sahasrabuddhe et al. Cancer 2012; 118: Risk of HCC increased 2-fold at CD4+ T cell count of <500 cells/µl and plateaus at <200 cells/µl. Hence immunodeficiency important Brau et al. J Hepatol 2007; 47:

17 HIV positive patients who received care in the Veterans Affairs (VA) health care system nationally between 1996 and 2009 (n = 24,040 in 2009) 17

18 Diabetes/ NAFLD Insulin resistance common amongst HIV patients ANRS CO13 HEPAVIH cohort The HOMA index and age, were independently associated with the risk of HCC occurrence in a prospective cohort of 244 HIV/HCV-co-infected patients with cirrhosis and without treated diabetes. Salmon et al J Hepatol 2012 Apr;56(4):

19 HIV and Tat 1 HIV-1 Tat protein stimulates cell proliferation, inhibits apoptosis, displays angiogenic functions. Tat transgenic mice constitutively express Tat in all tissues. When exposed to a general carcinogen urethane there was significantly more liver tumours in the transgenic mice compared to control mice. Eur J Cancer 2004 Jan;40(2):

20 Prevention of cirrhosis and HCC in HIV infected patients 20

21 Screening for HCC European Guidelines (EACS) recommend in HIV infected patient with HCV related cirrhosis 6 monthly liver ultrasound surveillance 6 monthly serum alpha-fetoprotein measurement Rockstroh et al. HIV Med 2008; 9:

22 Failure rates in HCC surveillance in general practice 178 cases of HCC at a single centre Retrospective chart review Only 20% had some form of surveillance Surveillance 6x more likely if followed up by hepatologist Surveillance 7x less likely in alcoholic patients Singal AG et al. Cancer Prev Res (Phila) 2012;5: KAHS01

23 Requirements of a successful screening test Disease sufficiently common Disease poses serious risk of morbidity and mortality Inexpensive test Able to be applied repeatedly Minimally invasive Minimal risk to screened population Population must be accessible and recognizable Standardized recall policies Effective treatment for those identified with disease

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25 Staging systems for HCC System Hepatic AFP P.S Tumour burden BCLC CPS No Yes Tumour size, number, PVT Okuda Ascites No No Tumour size, number, metastases, PVT Albumin Bilirubin TNM No No No Tumour size, number, metastases, PVT CLIP CPS Yes No Tumour > 50% of liver, number, PVT CUPI Ascities Yes Symptoms TNM Bilirubin AP JIS CPS No No TNM GETCH Bilirubin Yes Yes PVT AP

26 Treatment Local ablative therapy Surgical resection Chemotherapy Transplantation Oncologist 2013;18(5): doi: /theoncologist Epub 2013 May

27 Post- TACE + RFA at 33 month TACE + RFA Pre-Rx Post- TACE

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31 Transplantation Multicenter Italian Experience in Liver Transplantation for Hepatocellular Carcinoma in HIV-Infected Patients. Multicenter study (3 Italian transplant centers in northern Italy) 30 HIV-positive patients affected by HCC who underwent LT with 125 HIVuninfected patients who received the same treatment from September 2004 to June RESULTS: HIV-infected patients were younger, they were more frequently anti-hcv positive, and a higher number of HIV-infected patients presented a coinfection HBV-HCV. Pre-LT treatments (liver resection and or locoregional treatments) were similar between the two groups. Histological characteristics of the tumor were similar in patients with and without HIV infection. No differences were observed in terms of overall survival and HCC recurrence rates. CONCLUSION: LT for HCC is a feasible procedure and the presence of HIV does not particularly affect the post-lt outcome. 31

32 HCC: the greatest obstacle to knowledge is not ignorance it is the illusion of knowledge Key messages Increasing recognition of liver as a cause of disease burden : thus screening/ investigation critical Co-ordination of HIV/ surgery/ hepatology/ oncology/ palliative medicine Rapidly improving sophistication of cross-sectional imaging Evidence strength equivocal - urgent need for better trials Role of transplantation and surgery Heterogeneity in imaging/ treatment modalities Selection of patient critical Concept of field change - tumour biology: Individualised therapy

33 Molecular classification of HCC Genomic profiling from the tumor Hoshida Y et al. Cancer Res 2009 Villanueva A et al. Gastroenterology 2008 Chiang DY et al. Cancer Res 2008

34 Molecular classification of HCC Prognostic Gene Signatures from adjacent liver Gene Signature from cirrhotic tissue (n=186 genes) HCC development (HCV-cirrhosis, n=216) Survival (Resected patients, n=225) Chiang DY et al. Cancer Res 2008, Hoshida et al. NEJM 2008,Villanueva A et al. Gastroenterology 2012, Hoshida Y et al. Gastroenterology 2013

35 Final thought knowing is not enough, we must apply willing is not enough we must do Johann Wolfgang von Goethe ( )